The human TSH beta gene is expressed only in the thyrotrophs of the anterior pituitary where it is regulated by hypothalamic hormones, cyclic AMP as well as thyroid hormone. Recent studies have indicated that TRH and cyclic AMP mediate their transcriptional action in large part through changes in phosphorylation of the specific pituitary factor pit-1 which binds to a region upstream of the start of transcription. In contrast, thyroid hormone mediates its inhibition through binding to a regulatory element downstream of the start of transcription in the first untranslated exon. Recent studies have indicated that the thyroid hormone receptor interacts with other factors in the mediation of hormone action. Such factors include the proto-oncogenes c-fos and c-jun which are the heterodimeric constituents of AP-1. Various transcriptional studies have indicated that c-fos augments thyroid hormone induced inhibition of transcription, whereas c-jun blunts such effect. Thus, control of the relative cellular levels of these 2 proto-oncogenes may play a major role in modulating thyroid hormone inhibitory responses. We have recently optimized a primary anterior pituitary cell culture system to reexamine the positive and negative regulation of human TSH beta transcription in native thyrotropic transcription factors which are currently being elucidated.